Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof

Abstract

The present invention provides tricyclic compounds, and pharmaceutically acceptable salts thereof, having antimitotic activity, anti-multidrug resistance activity, for example P-glycoprotein inhibition, and antitumor activity, and which inhibit paclitaxel sensitive and resistant tumor cells. Also provided are methods of utilizing these compounds for treating tumor cells and inhibiting mitosis of cancerous cells.

What is claimed is: 
     
       1. A method of treating a patient diagnosed with cancer comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt of the compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein both B and C rings may be completely or partially saturated with respect to bonds 4a-8a, 5-6 and 7-8; the C ring may have an R 4  attached to the C ring at positions 5, 6, 7 or 8, or a combination of one or more of these positions depending on the saturation level of the C ring and wherein R 4  may be the same or different when attached to a plurality of the 5, 6, 7, or 8 positions of the C ring; 
         R 1 and R 2  each independently is one of (a) a hydrogen (H), (b) an alkyl having from one to ten carbon atoms and having a straight or branched configuration, and wherein the alkyl is partially or completely saturated, or a substituted alkyl having from one to ten carbon atoms, (c) a cycloalkyl having from three to ten carbon atoms, or a substituted cycloalkyl having from three to ten carbon atoms, (d) an alkylcycloalkyl, or a substituted alkylcycloalkyl, (e) an aryl, or a substituted aryl, (f) an alkylaryl, or a substituted alkylaryl (g) a heteroaryl, or a substituted heteroaryl, (h) an alkylheteroaryl, or a substituted alkylheteroaryl, (i) an aromatic, or a substituted aromatic, and (j) a heteroaromatic, or a substituted heteroaromatic, and wherein each substituent of any said substituted group is the same or different and is selected from the group consisting of a straight or branched alkyl, alkenyl, or alkynyl, a cyclic or alicyclic group having from one to six carbon atoms, a heterocyclic group having from one to six carbon atoms, an alkoxy group, an aryloxy group, an alkyloxyaryloxy group, an aryl group, an amine, a halogen, a phenol, a naphthalene, a piperidine, a pyrrole, a ketone, a methylalkyl ketone, and a trifluoromethyl ketone, and wherein each of said substituents may itself be substituted, and wherein any of said substituents may be optionally attached by a CH 2  bridge, and wherein the substituent may be optionally partially or completely saturated or unsaturated when it is not represented by said halogen; 
         R 1  and R 2  are the same or different with the exception that R 1  and R 2  may not each be hydrogen at the same time; 
         R 3  is one of (a) a hydrogen (H), (b) an alkyl having from one to ten carbon atoms and having a straight or a branched configuration, and wherein the alkyl is partially or completely saturated; (c) an NH 2 , (d) an NHR 7 , (e) an NR 7 R 8 , (f) an OH, (g) an OR, (h) an SH, and (i) an SR, and wherein R is one of R 1 , and wherein R 7  and R 8  may be the same or different and is one of R 1 ; 
         R 4  is one of (a) R 1 , (b) a halogen, (c) a mono-, di-, tri- or tetra-substituted alkyl, and (d) an alkyloxy, and wherein R 1  is H or a lower alkyl and R 2  is H or a lower alkyl then R 4  is one of (a) a NR 6 R 7 , (b) a SR 6 , (c) a OR 6 , and (d) a CHR 6 R 7 , wherein R 6  and R 7  are one of R 1  and R 2 , and R 6  and R 7  are the same when said C ring is completely or partially saturated; 
         X is a sulfur (S); 
         Y is one of (a) a nitrogen (N), (b) an oxygen (O), (c) a sulfur (S), and (d) a CR 6 , wherein R 6  is one of R 1  and R 3 , and wherein when Y is  0  or S then either R 1  or R 2  is absent; 
         wherein when said C ring is partially saturated and X is a sulfur (S) and Y is a sulfur (S) and R 3  is a hydrogen (H) or a methyl, then (a) R 1  is not a methyl when R 2  is absent; and (b) R 2  is not a methyl when R 1  is absent; 
         wherein when said C ring is partially saturated and X is a sulfur (S) and Y is an oxygen (O) and R 3  is a methyl, then (a) R 1  is not an ethyl or a propyl when R 2  is absent; and (b) R 2  is not an ethyl or a propyl when R 1  is absent; 
         wherein when said C ring is partially saturated and X is a sulfur (S) and Y is a nitrogen (N) and R 3  is a methyl, then (a) R 1  is not a hydrogen (H) when R 2  is a butyl; and (b) R 2  is not a hydrogen (H) when R 1  is a butyl; and (c) R 1  and R 2  are not both an ethyl; 
         wherein when X is a sulfur (S) and Y is a nitrogen (N) and R 3  is a hydrogen (H), then neither R 1  nor R 2  is a substituted phenyl group; 
       
       for achieving a therapeutic response.